Loss Expressions Of Dusp6, Sprouty4and Sef In Endometria Of Adenomyosis And The Significance

BackgroudAdenomyosis is a prevalent, benign gynecologic condition in which endometrial tissue invades into the myometrium, causing myometrial inflammation and hypertrophy. It can result in debilitating pelvic pain (both cyclical and non-cyclical) and abnormal uterine bleeding. Multivariate analysis showed that the prevalence of adenomyosis was significantly associated with women’s age, gravidity and the presence of pelvic endometriosis. However, the mechanism of the disease is still unclear.Fibroblast growth factor2(FGF2, also called basic FGF) is one of the first confirmed angiogenesis-related growth factors. FGF2elicits its biological activities by binding to FGF receptors, and then activates series of intracellular signaling pathways, among which mitogen-activated protein kinases (MAPKs) pathway is the most important. Activated ERK1/2further phosphorylates other cytoplasmic substrates and nuclear transcription factors and finally triggers a spectrum of responses in target cells, including caryomitosis, differentiation, proliferation and migration.In recent years, studies proved that the activity of FGF signaling requires a tight control by different feedback inhibitors such as the Dual-specificity phosphatase6(Dusp6), Sproutys (SPRYs) and Similar expression to fgf genes (Sef)[6]ObjectiveThe expressions of Dusp6, Sprouty4and Sef in normal endometria and eutopic endometria of patients with adenomyosis were evaluated to explore the mechanism of endometriosis.Methods Endometria from30patients with adenomyosis and29controls without adenomyosis were employed in this study. The expressions of Dusp6, Srouty4and Sef were investigated by immunohistochemistry and in situ hybridization analysis.ResultsWe found that Dusp6, Sprouty4and Sef expressions were present in endometrial epithelial cells of normal endometria and eutopic endometria of adenomyosis. Weak immunostanings were noted in stromal cells in both endometria. By immunohistochemistry analysis, we found that eutopic endometria of adenomyosis showed significantly decreased Dusp6, Sprouty4and Sef proteins expressions compared with normal endometria (P<0.05). No cyclical change was noted either in normal endometria or in eutopic endometria of adenomyosis during menstrual cycle (P>0.05). By in situ hybridization analysis, we found that the mRNA expressions of Dusp6, Sprouty4, and Sef were down regulated in eutopic endometria of adenomyosis compared with normal endometria. The positive signal mostly localized in the cytoplasm of epithelial cells in both endometria, whereas stromal cells showed a very weak signal in positive cases (P<0.01).Conclusions1. Downregulation of Dusp6, Sprouty4and Sef, negative modulators of FGF2/ERK1/2signaling, were present in eutopic endometria of adenomyosis, which may play critical rules in the development of adenomyosis.2. No significant difference of Dusp6, Sprouty4and Sef expressions were noted between endometria of the proliferation period and secretion period in normal endometria or in eutopic endometria of adenomyosis. These data suggest that the expressions of Dusp6, Sprouty4and Sef may not regulated by estrogen or progesterone.